The present invention relates to novel solid oxidation catalysts which make possible in particular the oxidation of prochiral compounds, in particular the asymmetric epoxidation of prochiral olefinic double bonds, more particularly of a carbinol compound exhibiting an ethylenic double bond separated from the carbinol group by 0 to 1 C, preferably those of allyl alcohols, to their method of preparation and the use of these solid catalysts in epoxidation reactions.
The introduction of a chiral center onto organic molecules has quite considerable industrial potentialities. This is because natural products are normally chiral, with only one enantiomer exhibiting a useful biological activity. Medicaments, agrochemicals, cosmetics or more generally any molecule which is used in life sciences generally belong to this family of chiral compounds with one or more centers of asymmetry. The separation of the enantiomers from a racemic mixture is expensive, lengthy and not economically profitable. One of the solutions envisaged for improving this irrefutable fact was to find catalysts, which are predominantly homogeneous. These catalysts are generally transition metal complexes which exhibit chiral ligands. Numerous enantioselective catalytic reactions exist.
In particular, the synthesis of enantiopure epoxyalcohols, used in particular as precursors of active principles for pharmaceutical products, is very important industrially (B. E. Rossiter xe2x80x9cAsymmetric Synthesisxe2x80x9d, Academic Press, 1985, vol. 5, pp. 193-246; M. Bulliard and W. Shum, xe2x80x9cProceedings of the Chiral""95 USA symposiumxe2x80x9d 1995, pp. 5-8; U.S. Pat. No. 4,764,628).
The catalysts currently known for reactions of this type are generally chiral titanium compounds used in the homogeneous liquid phase, according to the principle proposed by Katsuki and Sharpless (J. Am. Chem. Soc., 1980, 102, 5974 and U.S. Pat. No. 4,471,130), and cannot be reused (in this document, the chiral compounds can also be tantalum, zirconium, hafnium, niobium, vanadium and molybdenum compounds and the like). See also Johnson and Sharpless xe2x80x9cComprehensive Organic Synthesisxe2x80x9d, Pergamon Press, 1991, vol. 7, pp. 389-436 and xe2x80x9cCatalytic Asymmetric Synthesisxe2x80x9d, edited by I. Ojima, VCH, 1993, 103-158; Gao, Sharpless et al., J. Am. Chem. Soc., 1987, 109, 5765-5780. However, these catalysts cannot be easily separated from the reaction medium and their separation is, in some cases, particularly harmful to the reaction yield. Furthermore, they cannot be recycled and they cannot be used in a continuous process.
Farrall et al. (Nouv. J. Chim., 1983, 7, 449) describe a tartrate grafted onto a polystyrene resin. A titanium alkoxide was grafted onto such a solid and similar results but ones much inferior to those described by Sharpless et al. were obtained. Another publication by Choudary et al. (J. Chem. Soc., Chem. Commun., 1990, 1186) also described the incorporation of titanium-based Sharpless complexes in a clay of montmorillonite type. The solid proved to be active in asymmetric epoxidation but was not recycled. A publication by Adam, Corma et al. (J. Mol. Catal. A., 1997, 117, 357) reports diastereoselective and non-enantioselective epoxidations of allyl alcohols with aqueous hydrogen peroxide solution catalyzed by titanium-comprising zeolites. However, in this case, the starting allyl alcohols are already chiral and the catalysts achiral. These catalysts were not recycled.
A. Corma et al. (J. Mol. Catal. A., 1996, 107, 225-234) have proposed a molybdenum catalyst supported in a zeolite with a chiral ligand. It would be possible to recycle this catalyst but its enantioselectivity is low.
An object of the present invention is to provide novel solid oxidation catalysts which can be easily and efficiently recycled.
A more particular object of the present invention is to provide heterogeneous catalysis for the oxidation of prochiral compounds which combines the following properties:
performances (rate of reaction, activity per catalytic site, reaction yield and selectivity, enantiomeric excess obtained) equal to or superior to those of the homogeneous catalysts currently used,
ease of separation from the reaction medium,
reusable, while retaining the performances, and
optionally usable in a continuous process.
A more particular object of the invention is to provide such heterogeneous catalysis for the asymmetric epoxidation of prochiral olefinic double bonds, in particular those of allyl alcohols.
A first subject-matter of the present invention is a solid oxidation catalyst comprising a metal compound of a pentavalent or hexavalent metal M, selected from the group consisting of tantalum, vanadium, niobium, chromium, molybdenum and tungsten, grafted to the surface of a solid oxide by at least one, preferably one, covalent bond between an oxygen atom of the solid oxide and the metal atom M, the grafted metal compound exhibiting at least two alkoxy groups bonded to the metal via the oxygen atom, preferably at least one of these alkoxy groups being chiral.
The preferred metals are tantalum, vanadium and niobium. The most preferred metal is tantalum.
The alkoxy groups OR bonded to the metal M via the oxygen atom are identical or different (different means that at least one of the R radicals is different from the others). The R radicals are C1 to C30, preferably C1 to C8, more preferably still C1 to C6, hydrocarbonaceous chains which can be aliphatic or unsaturated, optionally cyclic, in particular aromatic, and which can optionally be functionalized, for example by halide, alcohol or ester functional groups and the like. The R radicals are preferably selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclohexyl, vinyl, allyl, phenyl or trialkylsilyl (R3Sixe2x80x94; R=Me, Et, i-Pr or n-Bu).
According to a preferred form of the invention, at least 2 alkoxy groups bonded to the metal M belong to a polyol unit, in particular a triol or diol unit, preferably a diol unit. These polyol units confer on the catalyst a chiral group of high stability which cannot be easily displaced or exchanged under the effect of other molecules when the catalyst will be employed in an epoxidation reaction.
Mention may be made, among the chiral diol units which come under the present invention, of:
1,2-propylene glycol
2,3-butanediol
3,4-dimethyl-3,4-hexanediol
4,5-octanediol
2,3-hexanediol
1,3-di(p-nitrophenyl)propane-1,2-diol
2,4-pentanediol
tartaric acid esters, for example:
dimethyl tartrate
diethyl tartrate
diisopropyl tartrate
distearyl tartrate
diphenyl tartrate
tartaric acid diamide
N,N-dimethyl tartaric acid diamide
trans-1,2-cyclopentanediol
diethyl 1,2-cyclohexanediol-1,2-dicarboxylate
dimethyl 2,4-dihydroxyglutarate
ethyl N,N-diethyl tartrate monoamide
2,5-dioxo-3,4-octanediol
1,2-bisacetylethylene glycol
bis-2,2xe2x80x2-(2-hydroxycaprolactone)
binaphthol
1,2-bis(methoxyphenyl)ethane-1,2-diol.
Diethyl or diisopropyl tartrate units are preferred.
Generally, the metal compound grafted onto the solid oxide preferably comprises 4 alkoxy groups when the metal M is selected from tantalum, vanadium or niobium and 4 or 5 alkoxy groups when the metal is selected from chromium, molybdenum or tungsten, those optionally belonging to a polyol unit being included within these values.
The oxidation catalysts according to the invention can also be defined by their process of preparation. It is possible, for the preparation of the catalyst, to preferably start from a complex of the metal M.
The precursor complexes of tantalum or another metal, which are used to create the bond between the metal M and the oxygen of the support (solid oxide), comprise appropriate identical or different ligands, at least one of which can be substituted by an oxygen of the solid oxide, for example an oxygen of a siloxy group in the case of silica, for the formation of at least one covalent bond between an oxygen atom of the solid oxide and the metal atom M. The ligands can be in all or part, in particular completely, alkoxy groups as described above, including polyol groups, or nonalkoxy ligands which, at a subsequent stage in the grafting of the metal complex to the solid oxide, can be substituted by alkoxy groups. The complex can comprise more than one metal atom M but will preferably be monoatomic for this metal. These complexes can correspond to the following general formula:
(MXa)bLc
where:
M is the metal selected from tantalum, vanadium, niobium, chromium, molybdenum or tungsten
a is an integer ranging from 4 to 6, it being understood that, when a=6, M is chromium, molybdenum or tungsten and it being understood that it is possible to have a double or a triple bond
b is an integer ranging from 1 to 4
c is an integer ranging from 0 to 16
X are ligands which can be identical or different (different means that at least one of the ligands X is different from the others) and are selected from:
the above R radicals
OR as described above with respect to the alkoxy groups,
acac (acetylacetonate)
NR2, with R as above
halogen atom, in particular Cl, Br or I,
L is any neutral (neither anionic nor cationic) molecular ligand, for example EtOH, NH3, pyran, and the like.
Preferably b=1. Preferably c=0.
Mention may in particular be made, among the complexes which can be used, of those which follow:
[(CH3)3CCH2]3TAxe2x95x90CHC (CH3)3 or any compound exhibiting at least one Ta-C bond and preferably several of these bonds, in particular a compound of the TaR5 type, with R, which are identical or different, in particular identical, as above, preferably selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclohexyl, vinyl, allyl, phenyl or trialkylsilyl (R3Sixe2x80x94; R=Me, Et, i-Pr or n-Bu), such as, for example, Ta(Me)5;
Ta(OC2H5)5 or more generally Ta(OR)5, with R identical or different, in particular identical, as above:
Ta(acac) (OC2H5)4 or more generally Ta(acac)x(OR)5-x, at the same level with x=1 or 2 and R identical or different, in particular identical, as above;
TaCl5, TaBr5 or TaI5.
The operation is carried out in the same way with vanadium, niobium, chromium, molybdenum and tungsten, the appropriate precursors being chosen where tantalum is replaced with the chosen metal, taking into account its own valency, for example:
if M=V or Nb:
MR5, M(OR)5, M(acac)x(OR)5xe2x88x92x, or M(halogen)5 
if M=Cr, Mo or W:
MR6, M(OR)6, M(acac)x(OR)6xe2x88x92x or M(halogen)6 
with x=1 or 2
with R identical or different, preferably identical, as above.
By way of examples:
WCl6 
MoCl6 
W(OEt)6 
W(CH2C(CH3)3)3(xe2x89xa1CC(CH3)3).
The preferred substrate is silica. However, other inorganic oxides can be envisaged; for example alumina, silica/alumina, zeolites, including silicalites, titanium oxide, niobium oxide, tantalum oxide, mesoporous silicas, and the like. The solid oxide, for example silica, will preferably be such as obtained by an exhaustive heat treatment (with the intention of providing partial dehydroxylation and dehydration), for example between 200 and 1100xc2x0 C. for several hours (for example 10 to 20 hours). Of course, a person skilled in the art will take care not to exceed the decomposition temperature or stability limit temperature of the solid oxide which he has chosen to use. For silica, the dehydration is generally carried out between 200 and 500xc2x0 C. to 800xc2x0 C., preferably between 400 and 800xc2x0 C., e.g. at 500 or at 700xc2x0 C. approximately, in particular if it is desired to obtain, in addition, the formation of surface siloxane bridges.
According to an advantageous form of the invention, the support, in particular silica, can be treated, before grafting the metal complex, with organosilicon compounds. These compounds include methylpolysiloxanes, such as hexamethyldisiloxane or octamethylcyclotetrasiloxane, methylpolysilazanes, such as hexamethyldisilazane (the preferred), or hexamethyl-cyclotrisilazane, chlorosilanes, such as dimethyldichlorosilane, trimethylchlorosilane, methyl-vinyldichlorosilane or dimethylyinylchlorosilane, or alkoxysilanes, such as dimethyldimethoxysilane, dimethylyinylethoxysilane or trimethylmethoxysilane.
The complex can be transferred onto the solid oxide in particular by sublimation or by impregnation in solution.
In the case of sublimation, the organometallic complex in the solid state is heated, preferably under vacuum (or under an inert gas) and under temperature conditions which provide for its sublimation and its migration in the vapor state onto the solid oxide, which is preferably itself in the pulverulent state or in the form of pellets or the like. Sublimation is in particular carried out between 50 and 150xc2x0 C., preferably at approximately 80xc2x0 C. The deposition can be monitored, for example by infrared spectroscopy. The grafting takes place by reaction of the complex with the functional groups of the support (OH, Si-O-Si, and the like). The solid will preferably be maintained at a temperature greater than or equal to ambient temperature.
It may be desirable to remove, by reverse sublimation, the excess unreacted complex which has simply been adsorbed at the surface of the oxide.
The grafting of the metal complex on the solid oxide can also be carried out by impregnation, a suspension of solid oxide and the metal complex being brought directly into contact. The suspension is preferably formed of solid oxide in a solvent, in particular a non-polar solvent, such as pentane. The whole reaction is preferably carried out under an inert atmosphere, e.g. argon. The grafting reaction is in particular carried out with stirring for several hours, the solid subsequently being filtered off, washed and dried, and stored under an inert atmosphere.
If it is desired to prepare a catalyst comprising alkoxy groups, it is advisable to subsequently treat the solid obtained with an alcohol, selected in particular from ethanol, methanol, isopropanol and butanol, preferably with vapors of an alcohol, in particular of one of those mentioned above. The most preferred form is the treatment with ethanol vapors. The reaction can be carried out in particular in a temperature range extending from 25 to 150xc2x0 C. for several hours, in particular at least 5 hours. The amount of alcohol introduced into the receptacle comprising the silica or another solid oxide modified by the metal compound should preferably be greater than 0.1 mol of alcohol per gram of silica or other solid oxide. After the heat treatment, the solid is preferably treated under dynamic vacuum, in particular lasting at least 5 hours at 150xc2x0 C. This treatment with an alcohol is not absolutely necessary, in particular if the starting material is a precursor complex already having alkoxy groups in order to graft it to the silica.
A subject-matter of the invention is thus the oxidation catalysts which can be obtained by the implementation of the process which has just been described.
More particularly, the invention is targeted at a chiral solid catalyst which makes possible in particular the oxidation of prochiral compounds, in particular the asymmetric epoxidation of prochiral double bonds, preferably those of carbinol compounds exhibiting an ethylenic double bond which is separated by 0 to 1 carbon atoms from the carbinol group, in particular allyl and homoallyl alcohols, in order to produce chiral epoxyalcohols. The targeted reaction is an enantioselective reaction.
In this application, use is made of a solid catalyst in accordance with the preferred form indicated above, namely comprising a polyol unit, preferably a diol unit. For its preparation, the starting materials are a precursor catalyst, as defined above by its characteristics or its process of preparation, preferably comprising alkoxy groups, more particularly having from 4 to 5 alkoxy groups, and a chiral polyol, in particular a chiral diol, preferably selected from those mentioned above, so as to exchange at least two OR groups by the polyol, in particular the diol, and thus to form the polyol or diol unit connected to the metal via oxygen atom(s).
The amount of chiral diol added should preferably be adjusted so as to obtain a diol:metal molar proportion of at least 0.5, in particular of between 0.5 and 3, it being known that higher proportions may be effective but are not essential. In the case of a tantalum catalyst, with diethyl tartrate as chiral diol, the optimal proportion is [tartrate:Ta] between 1 and 2. This makes it possible to prepare a catalyst which will result in a good epoxide yield and in an advantageously enantiomeric excess, for example in the case of the epoxidation of allyl alcohol to glycidol or of trans-2-hexen-1-ol to propyloxirane-methanol.
This exchange or substitution of OR group or more generally X group, as defined above, by a diol is preferably carried out in a solvent for the diol used, e.g. dichloromethane or pentane, these two solvents being, for example, well suited to the case of diethyl tartrate and of diisopropyl tartrate. The reaction medium comprising the diol and the solid oxide to which the metal compound is grafted is preferably kept stirred for a sufficient time until the relevant chiral catalyst is obtained, generally more than 10 or 15 hours (up to 48 hours), the medium being maintained at low temperature, in particular less than or equal to 0xc2x0 C., preferably between 0 and xe2x88x9220xc2x0 C. approximately.
The medium obtained, comprising the catalyst, can be used as is for the epoxidation reaction. While awaiting its use, it is preferable to store the catalyst at low temperature, as indicated, and preferably between 0 and xe2x88x9220xc2x0 C. It is also possible to filter the catalyst. In particular, for long-term storage, it is preferable to filter off the catalyst and to store it under cold conditions, in particular between 0 and xe2x88x9240xc2x0 C.
Another subject-matter of the invention is thus this method of functionalization of the alkoxide-comprising oxidation catalysts and the chiral solid catalysts capable of being obtained by the implementation of this method.
This chiral solid catalyst, based on tantalum or on another metal grafted to the surface of silica or the like, is used in particular in the epoxidation of carbinol compounds as defined above, preferably of allyl alcohols, with organic hydroperoxides as epoxidation agents, as is fully known per se. They are usually aliphatic hydroperoxides, which may be mono- or polyhydroperoxides, most commonly not having more than two hydroperoxy groups. Monohydroperoxides, in particular having from 1 to 20 carbon atoms, and more particularly from 1 to 12 carbon atoms, remain the commonest. Use is preferably made of hydroperoxides Rxe2x80x3OOH, such as in particular Rxe2x80x3=cumyl, tert-butyl, triphenylmethyl, n-butyl, methyl, ethylphenyl, pinanyl or trityl.
The enantiomeric excesses are of the same order of magnitude as those obtained with titanium in homogeneous catalysis. However, highly advantageously, the catalyst is filtered off and is reused for a fresh catalytic test and similar results are then obtained. The recycling can be carried out several times without a significant loss in activity or in stereoselectivity. Furthermore, it has been possible to demonstrate that the tantalum or other metal does not pass into solution and that the solid retains its same content of tantalum or other metal after several recycling operations. Surprisingly, if the same experiment is carried out with titanium complexes, a very low activity without an enantiomeric excess is then obtained, demonstrating, if it were necessary, the entirely unexpected nature of the invention.
Another subject-matter of the present invention is thus a method for the oxidation of prochiral compounds, in which the prochiral compound, an oxidant and a solid catalyst according to the invention are brought into contact and are reacted together. A particular subject-matter of the invention is a method for the asymmetric epoxidation of prochiral olefinic double bonds of a compound to be epoxidized, more particularly of a carbinol compound exhibiting an ethylenic double bond separated from the carbinol group by 0 to 1 C, preferably those of allyl alcohols, in which method the prochiral compound to be oxidized, in particular the allyl alcohol or the like, is brought into contact and is reacted together with a chiral solid catalyst according to the invention, comprising alkoxy groups and a group of the chiral polyol type, preferably chiral diol type, and an oxidant, in particular organic hydroperoxide or hydrogen peroxide.
The present invention is targeted in particular at the asymmetric epoxidation of allyl alcohols in general, unsubstituted or substituted, including polysubstituted, by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, CnH2n+1 alkyl groups with n=5 to 15, cyclohexyl, vinyl, allyl, phenyl or trialkylsilyl (R3Sixe2x80x94; R=Me, Et, i-Pr or n-Bu).
Mention may particularly be made, among the allyl alcohols which come under the present invention, of:
base allyl alcohol (2-propen-1-ol): CH2xe2x95x90CHCH2OH
allyl alcohols substituted in the 2-position: CH2xe2x95x90C(R)CH2OH
geraniol
nerol
linalol
allyl alcohols monosubstituted in the 3E-position: CH(R)xe2x95x90CHCH2OH
allyl alcohols monosubstituted in the 3Z-position: CH(R)xe2x95x90CHCH2OH
allyl alcohols disubstituted in the (2 and 3Z or 3E)-positions: CH(R1)xe2x95x90C(R2)CH2OH
allyl alcohols disubstituted in the (3, 3)-positions: C(R1)(R2)xe2x95x90CHCH2OH
allyl alcohols trisubstituted in the (2, 3, 3)-positions: C(R1)(R2)xe2x95x90C(R3)CH2OH
allyl alcohols monosubstituted in the 1-position: CH2xe2x95x90CHCH(R)OH
allyl alcohols disubstituted in the (1, 1)-positions:
CH2xe2x95x90CHC(R1)(R2)OH
allyl alcohols disubstituted in the (1, 2)-positions: CH2xe2x95x90C(R1)CH (R2)OH
allyl alcohols disubstituted in the (1 and 3Z or 3E)-positions: CH(R1)xe2x95x90CHCH(R2)OH
allyl alcohols trisubstituted in the (1, 1, 2)-positions: CH2xe2x95x90C(R1)C(R2)(R3)OH
allyl alcohols trisubstituted in the (1, 1 and 3Z or 3E)-positions: CH(R1)xe2x95x90CHC(R2)(R3)OH
allyl alcohols trisubstituted in the (1, 2 and 3Z or 3E)-positions: CH(R1)xe2x95x90C(R2)CH(R3)OH
allyl alcohols trisubstituted in the (1, 3, 3)-positions: C(R1)(R2)xe2x95x90CHCH(R3)OH
allyl alcohols tetrasubstituted in the (1, 1, 2 and 3Z or 3E)-positions: CH(R1)xe2x95x90C(R2)C(R3)(R4)OH
allyl alcohols tetrasubstituted in the (1, 1, 3, 3)-positions: C(R1)(R2)xe2x95x90CHC(R3)(R4)OH
allyl alcohols tetrasubstituted in the (1, 2, 3, 3)-positions: C(R1)(R2)xe2x95x90C(R3)CH(R4)OH
allyl alcohols pentasubstituted in the (1, 1, 2, 3, 3)-positions: C(R1)(R2)xe2x95x90C(R 3)C(R4 )(R5)OH with R, R1, R2, R3, R4 and R5 selected, independently from one another, from:
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, CnH2n+1 alkyl groups with n=5 to 15, cyclohexyl, vinyl, allyl, phenyl or trialkylsilyl (R3Sixe2x80x94; R=Me, Et, i-Pr or n-Bu).
The substrate to be oxidized, in particular to be epoxidized, for example allyl alcohol, is subsequently introduced into the medium (solvent+catalyst, maintained at a temperature of between +20 and xe2x88x9220xc2x0 C., preferably between 0 and xe2x88x9220xc2x0 C.) in a proportion such that the [substrate:metal] molar ratio is in particular between 1 and 10 000, preferably between 2 and 1 000, preferably between 4 and 200, in particular in the case of the epoxidation of an allyl alcohol catalyzed by a solid prepared from a compound of tantalum or other metal.
Throughout the duration of the epoxidation reaction, the reaction medium is preferably maintained between +20 and xe2x88x9220xc2x0 C., in particular between 0 and xe2x88x9220xc2x0 C.
The solvent used for the epoxidation reaction is preferably nonpolar and can be, for example, dichloromethane, pentane, hexane, and the like. This solvent can be distilled beforehand. It must, in any case, be employed carefully dehydrated; for this, it can be stored over a 3 xc3x85 or 4 xc3x85 zeolite sieve, itself well dehydrated beforehand (for example by heat treatment under vacuum at 300xc2x0 C. for at least 15 hours). The amount of solvent used is adjusted according to the concentration of allyl alcohol desired in the reaction medium at the beginning of the reaction. A concentration of allyl alcohol of at least 0.1M in the solvent is advisable. When the solvent is introduced into the reactor in order to suspend the solid (supported metal compound) a dehydrating agent, such as zeolite 3 xc3x85, preferably as a powder and well dehydrated beforehand, can be added to the reaction medium.
The oxidant is introduced slowly into the reaction medium. The epoxidation agents used are described above and are advantageously organic hydroperoxides ROOH, such that R=cumyl, tert-butyl, triphenylmethyl, xcex1-phenylbenzyl, xcex1, xcex1xe2x80x2-methylphenyl-benzyl, pinanyl, n-butyl or methyl, and optionally hydrogen peroxide H2O2, preferably in an anhydrous medium. These oxidants are preferably carefully dehydrated before being introduced into the reaction medium, for example over zeolite. It is preferable for the [oxidant:substrate to be epoxidized] molar ratio to be greater than 1 in order to obtain as great a conversion as possible of the substrate to epoxide. In the examples mentioned below, the value of this [oxidant:substrate to be epoxidized] ratio is approximately 2.
The mixture is subsequently left to stir, in particular for 4 to 48 hours, while keeping the temperature constant, e.g. at a value fixed between +20 and xe2x88x9220xc2x0 C. The reaction medium is subsequently filtered in order to collect, on the one hand, the solid, and, on the other hand, the filtrate. The solid is washed several times with the solvent and the liquid phases are combined together. The product can then be isolated and the solvent recycled.
It should be noted that, in the present application, proportions or ratios refers to molar proportions or molar ratios.